Alzheimer's disease is associated with two main types of abnormalities in the brain, plaques and neurofibrillary tangles. Our lab, like most labs trying to develop new treatments for Alzheimer's disease, has focused on the plaques up to this point. Based on a number of recently completed studies, we are proposing to shift our focus to the neurofibrillary tangles. Based on preliminary evidence that brain levels of copper affect the development of neurofibrillary tangles, the hypothesis is specifically focused on the relationship between copper and tangles. OBJECTIVES: 1) We will determine if copper can act directly on the precursor of the tangle, a brain protein named tau. 2) We will determine if the individuals baseline level of copper affects their ability to respond to the treatment, 3) we will determine if copper has an effect on the type of tau associated with sporadic Alzheimer's disease or the type of tau associated with some forms of hereditary frontotemporal dementia. 4) we will determine if a treatment which prevents protein misfolding can be used to enhance the effects of copper modulating therapy. PLAN: Experiments will be conducted in mice which are genetically engineered to express aspects of Alzheimer's pathology. Mice will be given treatments that raise or lower brain copper levels, and the effects on tangle pathology and memory function will be measured. METHODS: Standardized tests of mouse behavior, brain concentrations of disease- associated proteins, tests of cognitive function. FINDINGS TO DATE: Copper seems to increase tau phosphorylation and worsen memory in mice with neurofibrillary tangles. CLINICAL RELEVANCE: These experiments are designed to lead to clinical trials of copper-lowering treatment for Alzheimer's disease and related dementias. RELEVANCE TO THE VA'S MISSION: Development of safe, effective therapies for Alzheimer's disease and frontotemporal dementia is within the VA mission. Since neurofibrillary tangles are also seen in traumatic brain injury (TBI), this work may have additional relevance to the VA mission.